J . Med. Chem. 1991,34, 1560-1570
1560
previously described.l6vZ6 ICm values were determined with log-phase cultures in S w e l l microculture plates and are calculated as the nominal drug concentration required to reduce the cell density to 50% of control values, with eight control cultures on each microplate. For P388 cultures, drug was present throughout the growth period (72 h), and final cell densities were determined by wing a minor modification of the M" method of Mossman.n For AA8 and UV4 cultures, drug exposure was terminated after 18 h by washing three times with fresh medium. Cultures were grown for a further 72 h before determining cell density by staining with methylene blue.28 Acknowledgment. This work was supported b y the Auckland Division of the Cancer Society of New Zealand, (26) Baguley, B. C.; Wilson, W. R. Eur. J . Cancer Clin. Oncol. 1987, 23, 607. (27) Mossman, T. J. Immunol. Methods 1983, 65, 55. (28) . . Finlav. G . J.:. Baeulev. - . B. C.: Wilson, W. R. Anal. Biochem. 1986,-22,655. (29) Finlay, G. J.; Baguley, B. C.; Wilson, W. R. Eur. J. Cancer Clin. Oncol. 1986,22, 655. 1
the Medical Research Council of New Zealand, and Pharmol Pacific Ltd. The authors thank Susan Pullen and Michael Chin for cytotoxicity testing and Lynden Wallis for preparation of the manuscript. Registry No. 6.2HC1, 133041-48-2; 7.2HC1, 133041-49-3; 8. 2HC1, 133041-50-6; 9.2HC1, 133041-51-7; 10.2HC1, 133041-52-8; 11.HC1, 133041-53-9; 12.HC1, 133041-54-0; 13.HC1, 133041-55-1; 14.HC1, 133041-56-2; 15.HC1, 133041-57-3; 16.HC1, 133041-58-4; 17.HC1, 133041-59-5; 18.2HC1, 133041-60-8; 19,133041-62-0; 20, 133041-64-2; 21, 133041-66-4; 22, 133041-68-6; 23, 103-90-2; 24, 350-46-9; 25, 2687-40-3; 26, 2687-41-4; 27, 133041-69-7; 28, 133041-70-0; 29, 92961-98-3; 30, 93538-06-8; 31, 462-06-6; 32, 122-04-3; 33, 2195-47-3; 34, 133041-71-1; 35, 133041-72-2; 36, 133041-73-3; 37, 133041-74-4; 38, 133041-75-5; 39, 133041-76-6; 40,133041-77-7;41,133041-78-8; 42,133041-79-9; 43,133041-80-2; 44,133041-81-3; 45,100132-31-8; 46,133041-82-4; 47,133041-83-5; 48,133041-84-6; 49,133041-85-7; 50,133041-86-8; 51,133041-87-9; 52, 16331-48-9; 53, 2067-58-5; 54, 133041-88-0; 55, 133041-89-1; 56, 133041-90-4; 57, 7575-35-1; 58, 133041-91-5; 59, 15944-88-4; 60,133041-92-6; 61, 133041-93-7;62,133041-94-8; 63,133041-95-9; 4-chloroquinoline, 611-35-8.
5-Lipoxygenase Inhibitors: The Synthesis and Structure-Activity Relationships of a Series of 1-Phenyl-3-pyrazolidinones' Dennis J. Hlasta,*J Francis B. Casey,' Edward W. Ferguson,t Sally J. Gangel1,t Martha R. Heimann,t Edward P. Jaeger,t Rudolph K. Kullnig,s and Robert J. Gordon$ Departments of Medicinal Chemistry, Pharmacology, and Molecular Characterization, Sterling Research Group, Rensselaer, New York 12144. Received October 23, 1990
A series of analogues of the 5-lipoxygenase inhibitor 1-phenyl-3-pyrazolidinone(phenidone, la) has been prepared via two complementary new synthetic methods. The reaction of various electrophiles with the dianion of la or with an N-silylpyrazolidinone anion gave the desired 4-substituted pyrazolidinones (Scheme I and 11). A new procedure was developed for the resolution of 4-substituted pyrazolidinones (Scheme V). A regression study on 21 compounds in this series showed a correlation of increased inhibitor potency (PIC,) with increased compound lipophilicity (log P ) and with an N-phenyl electronic effect as measured by the 13C NMR chemical shift parameter CNMR1' (R2= 0.79). The most potent 5-lipoxygenase inhibitor in this series was 4-(ethylthio)-l-phenyl-3-pyrazolidinone (In) with an IC, of 60 nM. Another member of this series, 4-(2-methoxyethyl)-l-phenyl-3-pyrazolidinone (If, IC, = 0.48 wM), although less potent than In, was better tolerated in the whole animal relative to phenidone (la) and also displayed good oral activity in two models of 5-lipoxygenase inhibition. On the basis of a structureactivity relationship study, a mechanism for the inhibition of 5-lipoxygenase by this class of inhibitors was proposed.
The identification of the leukotrienes (LTC4, LTD4, LTE4) as mediators i n the pathophysiology of allergic disease has attracted the interest of many laboratories t o discover agents which either antagonize the leukotriene receptor(s)* or inhibit leukotriene b i o ~ y n t h e s i s . ~Since 5-lipoxygenase (5-LO) oxidizes arachidonic acid to 5hydroperoxyeicosatetraenoicacid (5-HPETE) in the first step of t h e leukotriene pathway i n the arachidonic acid cascade, inhibitors of this enzyme should prevent leukotriene biosynthesis and therefore prove useful in the treatment of allergic asthma. Phenidone (la) a n d BW-755C were reported to inhibit 5-LO b o t h i n vitro4J a n d orally ex vivo.6 More recently the phenidone analogues A-53612 @a)' and A-652608 have been reported to possess improved selectivity for &LO, compared t o t h a t of phenidone, as well as oral activity in Department of Medicinal Chemistry. Department of Pharmacology. I Department of Molecular Characterization. 0022-2623/91/ 1834-1560$02.50/0
Scheme I. 4-Substituted Pyrazolidinones via the Dianion 18 (Methods A and B) Melhod A n
0
L
Method B
J 18
8% v v HMPA added
lblp,6
E' = R. X Ketones and Disullider
the inhibition of leukotriene biosynthesis. We now report our findings in the chemistry and in the structure-activity (1) Presented in part at the 199th National Meeting of the Am-
erican Chemical Society, Boston, MA, April 22-27, 1990; MEDI 77. (2) Musser, J. H.; Kubrak, D. M.; Chang, J.; DiZio, S. M.; Hite, M.; Hand, J. M.; Lewis, A. J. J. Med. Chem. 1987,30,400 and cited references. 0 1991 American Chemical Society
5-Lipoxygenase Inhibitors
Journal of Medicinal Chemistry, 1991, Vol. 34, NO.5 1561
relationships (SAR) of a series of phenidone analogues.
Scheme 11. 4-(2-Methoxyethyl)pyrazolidinonesvia the N-Silylpyrazolidinone Anion 21 (Method C) 0 TBDMS-Ci
Phenidone ( l a )
0
BW.755C
n
19
A-65260
Chemistry The formation of dianions from secondary amidesBor carboxylic aciddohas been known for some time. We have found that treatment of phenidone (la) with 2.4 equiv of
20
I
I A.53612 @a)
1) LOA
i
A,
2) BrCHzCH20CH3
c 3) H,O*, EIOH
kx
L
I
1
21
7. 11-16
Scheme 111. Synthesis of Pyridazinones 2a and 2P
n-butyllithium.N,N,N',N'-tetramethylethylenediamine complex in tetrahydrofuran at 0 "C was necessary for the formation of the dianion 18 (R,= H, see Scheme I, method A). Quenching experiments of the dianion 18 with D20 showed complete deuterium incorporation by NMR after reaction for 1 h at 0 "C. In the absence of TMEDA, no deuterium incorporation was detected at 0 "C and in ether after 4 h at room temperature only 50% conversion to the dianion was detected. Treatment of 18 with various electrophiles provided the desired 4-substituted pyrazolidinones (lb-p) in modest to good yields. 1-Phenyl-1Hpyrazol-3-0h 4 were the major products formed when poor alkylating agents were used. In some cases this could be obviated by the addition of 8% by volume of hexamethylphosphoramide (HMF'A) (method B). For example, ethoxyethyl derivative lg was prepared in 63% yield in the presence of HMPA, while in the absence of HMPA a 22% yield of lg was obtained along with 1-phenyl-lHpyrazol-3-014. This reaction was extended to the formation of dianion 18 (R, = CH#l which on treatment with bromomethyl methyl ether gave 4-methyl analogue 6. Attempts to form the dianion of 5-methyl- or 5,5-dimethyl-l-phenyl-3-pyrazolidinone, 1-(4-methylphenyl)-3Welton, A. F.; Holland, G. W.; Morgan, D. W.; ODonnell, M. Annual Reports in Medicinal Chemistry; Academic Press: 1989; Vol. 24, Chapter 7, p 61. Blackwell, G. J.; Flower, R. J. Prostaglandins 1978, 16, 417. Higgs, G. A.; Flower, R. J.; Vane, J. R. Biochem. Pharmacol. 1979,28, 1959. Foster, S. J.; McCormick, M. E.; Howarth, A. Agents Actions 1985, 17, 358. Brooks, D. W.; Kerdesky, F. A. J.; Holms, J. H.; Schmidt, S. P.; Basha, A,; Ratajczyk, J. D.; Martin, J. G.; Young, P. R.; Albert, D. H.; Dyer, R. D.; Bouska, J. B.; Carter, G.W.196th American Chemical Society National Meeting, Los Angeles, CA, September 25-30, 1988; MEDI 121. Brooks, D. W.; Basha, A.; Bhatia, P. A.; Ratajczyk, J. D.; Schmidt, S. P.; Albert, D. H.; Young, P. R.; Bouska, J. B.; Dyer, R. D.; Bell, R. L.; Carter, G. W. 198th American Chemical Society National Meeting, Miami Beach, FL, September 10-15, 1989; MEDI 87. Gay, R. L.;Hauser, C. R. J. Am. Chem. SOC. 1967,89, 1647. Creger, P. L.J. Am. Chem. SOC. 1967,89, 2500. The substituted 1-phenyl-3-pyrazolidinonestarting materials 19 were prepared from substituted phenylhydrazines and ethyl acrylates by the following method. Bennett, G. B.; Houlihan, W. J.; Mason, R. B.; Roach, J. B., Jr. J. Med. Chem. 1976,19, 715.
22
21
-5cH2cH ON
n-BuLi ' TMEDA (2.4 eq.1 P
THF, HMPA, 0 % BrCH2CH2CCH3
21
Scheme IV. Synthesis of 4-(2-Methoxyethyl)-5,5-dimethylpyrazolidinone 10
NaOEl
EIOH, PhCH3 rellux
0
0
10
9
pyrazolidinone, or l-(4-chlorophenyl)-3-pyrazolidinone11 were unsuccessful. These compounds, however, were obtained via the anion formed from 2-(tert-butyldimethylsilyl)-3-pyrazolidinones20 with lithium diisopropylamide in THF at -78 "C (see Scheme 11,method C).12 Treatment of anions 21 with 2-bromoethyl methyl ether at 0 "C or room temperature gave the desired trans-substituted 5(12) Subsequent to our work a patent application disclosed the use of this method on similarly substituted 3-pyrazolidinones,
Michno, D. M. Eur. Pat. Appl. EP 134,696,1985; Chem. Abstr., 1985, 103,79403k.
Hlasta et al.
1562 Journal of Medicinal Chemistry, 1991, Vol. 34, No. 5 Scheme V. Resolution of 4-(2-Methoxyethyl) 1-phenyl-3-pyrazolidinone( 1f )
-
y
HN+cH2cH20c~3 \
-
d"
N+cH2cH20cH, \
I+)CH3
toluene, rellux
2) HPLC separaton
3
OCONHCHPh
1 ) PhCHFCC-0
d"
23A. 238
11
PhNH2
toluene rellux
HN+cH2cH2cxH3 \
'd I*)
11, (4 11
methyl analogue 7 and phenyl substituted derivatives 11-16. The trans stereochemistry of 5-methyl analogue 7 was assigned by NOE difference experiments. Pyridazinone 2a was prepared by a literature procedure13 through the reaction of phenylhydrazine with ethyl 4chlorobutyrate in variable yields (10-27%). We have developed an improved two-step procedure (Scheme 111). Condensation of phenylhydrazine with diethyl succinate gave pyridazin-3,g-dione 22,14 which on reduction with lithium aluminum hydride gave pyridazinone 2a in 67 70 yield. The regioselectivity of the reduction reaction was confirmed by a NOESY experiment on 2a which displayed a crosspeak between the o-phenyl and the pyridazinone ring C6 protons. The dianion formation from 2a proceeded smoothly, which on alkylation (method B) gave the 4substituted pyridazine 2f in 50% yield. Acetylation of 1-methyl-1-phenylhydrazine with acetic anhydride and triethylamine in methylene chloride yielded acethydrazide 3.15 Pyrazolidinones l b and If were readily oxidized by m-chloroperbenzoic acid in methylene chloride to afford pyrazol-3-01s4b and 4f. Pyrazolidinone l b was N-methylated with sodium hydridemethyl iodide in DMF to give N-methylpyrazolidinone 5. 5,5-Dimethyl analogue 10 was prepared through the three-step procedure outlined in Scheme IV. The regiochemistry of the condensation reaction was confirmed by a NOESY experiment on 10 which showed a crosspeak between the o-phenyl and the C5 methyl protons. We wished to determine the enantio preference for inhibition of 5-lipoxygenase; however, a method for the resolution of racemic pyrazolidinones had not been reported. The formation of diasteromeric salts with chiral bases was unsuccessful since the pyrazolidinones are weak acids.16 We have found that adduct 23 can be formed in good yield by the thermal reaction of (R)-(+)-a-methylbenzylisocyanate with If (see Scheme V). Preparative HPLC afforded the two diastereomers 23, which on reaction with aniline in refluxing toluene gave the enantiomers (+)-lf and (-)-lf. We chose to trap the isocyanate generated in the thermal cleavage of the diastereomers 23 with aniline, a weak, poorly nucleophilic base, to avoid epimerization or pyrazolidinone ring cleavage. For example, attempted cleavage of the adduct 23 to If with sodium hydroxide in methanol at 0 O C for 30 min only gave pyrazolidinone ring cleavage. The optical purity of (+)-lf (13) (14) (15) (16)
Walther, W. Veroff. Wiss. Photo-Lab. 1965, 10, 159. Conrad, M.; Zart, A. Chem. Ber. 1906, 39, 2282. Fischer, E. Justus Liebig Ann. Chem. 1887, 239, 248. The pK, of phenidone ( l a ) is 9.35. Lee, W. E.; Brown, E. R. The Theory of the Photographic Process, 4th ed., Macmillian: New York, 1977; Chapter 11, p 321.
Table I. Physical Properties % vield recrvstn compd (method) mp, "C solvent" formulab lb 42 (A) 98-99 EA-C CllH1dN202 IC 50 (A) 82.5-83 T-H Cl2HlI3N202 Id 20 (A) 94.5-96 T-H C13H18N202 le 43 (A) 81-83 T-C C13H18N203 63 (B) 73.5-75 If 74-75.5 EA-H 1g 102-104 EA-H lh li 83-84 B-H 112-115 C lj EA-H lk 124-129 11 T-H 119-120.5 EA-C lm 115-117 EA-H 73.5-74.5 In EA-H 112-113.5 lo EA-H 131-133 1P EA 148.5-150.5 2a 2f 7C-72 EA-H EA-H 85-87 3 T-H 104-105.5 4b Et 91-93 4f oil (bp 154-155, 5 1.5 mmHg) 137-139 EA-H 6 E-H 7 65-66.5 E-H 66-67 8 E-H 9 55-56 oil 10 EA-H 11 95-96.5 EA-H 12 98-99.5 EA-E 13 88-89 E 14 64.5-66 EA 129-131 15 E 59-60 16 A 144-146 17 "A = acetonitrile, B = tert-butyl methyl ether, C = cyclohexane, E = ether, EA = ethyl acetate, Et = 95% ethanol, H = hexanes, T = toluene. *Carbon, hydrogen, and nitrogen analysis were within f0.4% of the theoretical values. See the Experimental Section. Reference 15. e C: calcd, 65.43; found, 64.94.
'd
Figure 1. ORTEP drawing of I f .
and (-)-lf was determined by chiral HPLC analysis on a Chiralcel OD column eluted with 2-propanol-hexanes mixtures. The optical purities of (+)-lf and (-)-lf were 99% and 8970,although the optical rotations were +94.0° and -94.7O, respectively. The lower optical purity of (-)-lf is presumably due to incomplete separation of the diastereomers in the difficult preparative HPLC separation of diastereomers 23. The physical properties of lb-p, 2a,f, 3,4b,f, and 5-17 are outlined in Table I. The X-ray crystal structure of (+)-lf was determined and is shown in Figure 1 in an arbitrary absolute configuration. The absolute configuration could not be determined due to the absence of significant anomalous ab-
Journal of Medicinal Chemistry, 1991, Vol. 34, No. 5 1663
5-Lipoxygenase Inhibitors Table 11. C-4 Substituent Effects on 5-Lipoxygenase Inhibition
compd phenidone (la) lb IC Id
R1
5-LO inhibn? ICm PM 0.52 (0.43-0.64) 0.59 (0.37-0.94) 0.28 (0.24-0.33) 0.26 (0.21-0.33) 0.52 (0.42-0.65) 0.48 (0.41-0.56) 0.35 (0.29-0.41) 1.03 (0.85-1.24) 0.15 (0.11-0.20)
H CH2OCH3 CH2OCH2CH3 CH20CH2CH2CHS le CH20CH2CHaOCH3 lf CH2CH2OCH3 If (+I CH2CH2OCH3 1f (4 CHzCHzOCHS le CH&H,OCH&H, lh CH2CH2OH >lb li CH&H2N(CHJZ >>lC 11 C(OH)(CH3)2 >lb lk C(0H)Phz 95% neutrophils) were stimulated with ionophore (A23187) for 15 min and the reaction was stopped with acetonitrile/methanol. Following a 30-min extraction period at room temperature, the sample was centrifuged (35000g, 5 "C) and the supernatant analyzed for LTB, by reverse-phase HPLC. ED,, values and 95% confidence limits were computed from the linear portions of the dose-response curves, with each dose administered to at least five animals. Inhibition of Leukotriene-Mediated Bronchoconstriction in Vivo. Guinea pigs were immunized with 1mg ovalbumin, and 3 mg alum used as an adjuvant. Two weeks later, each animal was anesthetized and prepared for the monitoring of tracheal pressure during mechanical ventilation. The guinea pig was pretreated iv with naproxen (10 mg/kg), pyrilamine (3 mg/kg), and propranolol (0.1 mg/kg),then challenged with ovalbumin (0.3 mg/kg iv). Test compound or vehicle was administered orally 1h prior to challenge. Maximum increases in tracheal pressure occurring within 20 min postchallenge were used for assessment of percent inhibition. EDsovalues and 95% confidence limits were computed from the linear portions of the dose-response curves,
J . Med. Chem. 1991,34, 157C-1577
1570
with each dose administered to at least eight animals. Acknowledgment. We acknowledge the contributions of the following individuals and their staffs: Raymond Everett and Jon Kimball for the toxicology, Frank Santillo and Jeffrey Hane for the optical purity determinations, and Stephen Clemens for the spectroscopy support. Registry No. l a , 92-43-3; (&)-lb, 133043-49-9; (*)-lc, 133043-50-2; (&)-ld, 133043-51-3; (&)-le, 133043-52-4; (*)-lf, 133043-53-5; (+)-lf, 133043-34-2; (-)-lf, 133043-35-3; (*)-lg, 133043-54-6; ( & ) - l h , 133043-55-7; ( i ) - l i , 133043-56-8; ( i ) - l j , 133043-57-9; (*)-lk, 133043-58-0; (*)-ll, 133043-59-1; (*)-lm, 13307 1-03-1; (&)-In, 133043-60-4; (*)-lo, 133043-61-5; (*)- 1 p, 133043-62-6;2a, 7190-52-5; (*)-2f, 133043-63-7;3,38604-68-1;4b,
133043-64-8; 4f, 133043-65-9; (*)-5, 133043-36-4; (*)-6,13304337-5; (*)-7, 133043-38-6; (*)-8, 133043-39-7; (*)-9, 133043-40-0; (*)-lo, 133043-41-1; (*)-11, 133043-42-2; (*)-12, 133043-43-3; (*)-13, 133043-44-4; (&)-14,133043-45-5; (*)-15, 133043-46-6; (*)-16, 133043-47-7; ( i ) - 1 7 , 133043-48-8; 19 (R3 = H, X = 4OCHzPh),6080-54-2; 20 (R3= H, X = 4-OCHzPh),133043-66-0; 22, 61446-43-3; HMPA, 680-31-9; 5-L0, 80619-02-9; (R)-(+)PhCH(CH,)NCO,33375-06-3; PhNH2,62-53-3; Br(CH.Jz0CH3, 6482-24-2; TBDMS-C1, 18162-48-6;Pd, 7440-05-3; PhNHNH2, 100-63-0; (CHJ,C=C(COOEt),, 6802-75-1. Supplementary Material Available: Tables listing crystal
data, atomic coordinates, thermal parameters,bond lengths and angles, and a stereoview of I f (5 pages). Ordering information is given on any current masthead page.
The Synthesis and Potassium Channel Blocking Activity of Some (4-Methanesulfonamidophenoxy)propanolaminesas Potential Class I11 Antiarrhythmic Agents Sean P. Connors,t Paul D. Dennis, Edward W. Gill,* and Derek A. Terrar Pharmacology Department, Oxford University, South Parks Road, Oxford O X 1 3QT, England. Received September 6, 1990
The synthesis of 22 (4-methanesulfonamidophenoxy)propanolaminesand their testing on isolated guinea pig cardiac myocytes, on isolated preparations from guinea pig atria, and on rat blood pressure are described. Secondary amines in the series (1 la-f) showed residual @-blockingactivity,whereas incorporation of N-methyl phenylalkyl and 4-phenyl alicyclic amine groups abolished @-blockingactivity but led to enhanced ability to block the channel conducting the delayed rectified potassium current, and hence produced an increase in the cardiac action potential duration (APD). Incorporation of hydrophobic C1 and CF3groups further enhanced potassium channel blocking activity. Compounds 81 and 8m produced a significant increase in APD at nanomolar concentrations, with no effect on cardiac muscle conduction velocity, and hence merit further investigation as Class I11 antiarrhythmicagents. Methylation of the methanesulfonamidogroup abolished channel-blockingactivity; 4-carboxy and 3-methanesulfonamidoanalogues retained activity but at a reduced level. Several years after its introduction as a 0-blocking agent it was observed' that sotalol, 1, produced a concentra-
1
3
tion-dependent increase of the cardiac action potential duration (APD) in a wide range of tissues, and it was this observation that prompted Vaughan Williams to designate a third category (class 111) of antiarrhythmic agenk2 This observation was not followed up immediately, but a resurgence of interest in sotalol (see ref 3 for a report on a recent symposium) occurred as a consequence of the increasing use of amiodarone (a compound that also increased cardiac APD) as an antiarrhythmic agent, and groups at Lilley: Pfiier? and Eisai6 have recently reported results of searches for more potent class 111 agents. Recently a report has been published' by another group describing the development of a mixed function class I1 and class I11 antiarrhythmic agent 2 which, like ours, is based on an oxypropanolamine analogue of sotalol. The
Berlex group sought to develop a mixed function compound on the grounds that a @-blocking(class 11) action would reduce the possibility of a sympathetically mediated triggering of an arrhythmia, and that the increased cardiac refractory period produced by a class I11 agent would prevent a reentrant rhythm from becoming established. Our approach was quite different. There is a clinical need for a drug to reduce the likelihood of an arrhythmia developing in the recovery period immediately following a myocardial infarction. Chamberlain8 has shown that during the 4 or 5 days following an infarction the risk of mortality is increased by the use of a P-blocking agent, as a consequence of an increased risk of heart failure. Under these circumstances the requirement is for a rapidly acting selective class I11 agent, devoid of class I or I1 actions. In general, as far as clinical use is concerned, the difficulty Singh, B. N.; Vaughan Williams, E. M. Br. J . Pharmacol. 1970, 39, 675.
Vaughan Williams, E. M. J. Clin. Pharmacol. 1984, 24, 129. Singh, B. N. (Ed.)Am. J. Cardiol. 1990, 65, 3A-88A. Steinberg, M. I.; Smallwood, J. K. Handbook of Experimental Pharmacology, Vol. 89; Antiarrhythmic Drugs; Vaughan Williams, E. M., Ed., Springer Verlag: Berlin, 1989; Chapter 17. Cross, P. E.; Arrowsmith, J. E.; Thomas, G. N.; Gwilt, M.; Burges, R. A.; Higgins, A. J. J . Med. Chem. 1990, 33, 1151. Katoh, H.;Nomoto, K.; Sawada, K.; Shoji, T. Eur. Heart J. 1988, 9, 1277. Morgan, T. K.; Lis, R.; Lumma, W. C.; Wohl, R. A,; Nickisch, K.; Phillips, G. B.; Lind, J. M.; Lampe, J. W.; Di Meo, S.V.; Reiser, H.J.; Argentieri, T. M.; Sullivan, M. E.; Cantor, E. J. Med. Chem. 1990, 33, 1087. Chamberlain, D. A. Br. Heart J . 1983, 49, 105.
* To whom correspondence should be addressed.
Rhodes Scholar. Present address: Medical Sciences Faculty, Memorial University of Newfoundland. 0022-2623/91/1834-1570$02.50/0
0 1991
American Chemical Society
